Abstract:
The p38 kinase plays a vital role in the inflammation mediated by tumor
necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) pathways and
inhibitors of p38 kinase provide effective approach for the treatment of
inflammatory diseases. Three dimensional quantitative structure activity
relationship (3D QSAR) studies involving comparative molecular field
analysis (CoMFA) were performed on 38 benzimidazolone derivatives as
p38 kinase inhibitors. CoMFA was performed using Sybyl software 6.7v.
Compounds were divided in to training and test set. The developed model
based on training set containing 28 compounds gave leave one out cross
validation q2 value of 0.648 and non cross validation r2 value of 0.980 and
standard error of estimate 0.119 for CoMFA. The steric and electrostatic
contributions are 61.6% and 38.4%. Additionally, the binding mode of the
high active compound at the active site of p38 MAP alpha kinase was
explored using LigandFit docking program and hydrogen-bonding
interactions were observed between the inhibitor and the target. The
details of amino acid interactions of the active site are discussed briefly.
The CoMFA model provided the most significant correlation of steric and
electrostatic fields with biological activities. The information rendered by
3D QSAR model may afford valuable clues to optimize the lead and
design new potential inhibitors.